This project is comprised of several clinical research studies designed to elucidate the neurobiology of PTSD, panic disorder, and social phobia, and to investigate potential new treatments for these serious anxiety disorders. Studies involving neuroendocrine and behavioral challenges with the anxiogenic neuropeptide agonist pentagastrin are aimed at determining the role of peripheral and central cholecystokinin in normal and pathological anxiety states. To date, we have determined that intravenous pentagastrin leads to increased anxiety and syndrome-specific symptoms in patients with social phobia and panic disorder, and that patients with these anxiety disorders are more sensitive to the anxiogenic effects of pentagastrin than healthy volunteers. Early data suggest that patients with PTSD also develop syndrome-specific symptoms (i.e., flashbacks) upon pharmacological challenge with intravenous pentagastrin. Ondansetron, a 5-HT3 antagonist that blocks the anxiogenic effects of CCK agonists in animal models, did not attenuate the effects of pentagastrin in patients with anxiety disorders. Early results from an ongoing study also suggest that treatment with selective serotonin reuptake inhibitors (SSRIs) is therapeutic in both panic disorder and social phobia, but that SSRIs do not attenuate the effects of intravenous pentagastrin. Pilot data in patients with PTSD suggest that gabapentin may have utility as an adjunctive medication in the chronic treatment of PTSD. Preliminary studies of right frontal 1 Hz repeated transcranial magnetic stimulation (rTMS) of the brain for the treatment of PTSD are promising, and a randomized, controlled trial has been initiated. Data with 1 Hz rTMS suggest that it acutely reduces cerebral metabolism in normal volunteers and reduces blood flow in depressed patients treated for two weeks, and preliminary data suggest the same effect in patients with PTSD. The relationship of these effects to improvement in PTSD symptoms remains to be elucidated.